A plasma kallikrein-kinin system is a series of reaction systems in vivo producing kinins which have various physiological activities. The plasma kallikrein-kinin system strongly participates in controlling the functions of living organisms. The system has a close relation with various other enzymatic reaction systems such as the renin-angiotensin system, the blood coagulating system, the fibrinolysis system, the complement system and the arachidonate cascade mainly for prostaglandin, leukotriene and thromboxane or catecholamine.
Kinins, such as bradykinin, which are the products of the kallikrein-kinin system have various physiological activities such as hypotension by dilation of peripheral blood vessels, increasing permeability of blood vessels, contraction and relaxation of smooth muscles, generation of pain, migration of leukocytes and liberation of catecholamine from the adrenal cortex. In addition, they are known as mediators for inflammation reactions including allergic reactions whereby their presence in living organisms is greatly significant. Accordingly, it is believed that substances which suppress the actions of kinins or inhibit the production thereof are useful as pharmaceuticals such as antiinflammatory agents, analgesic agents and antiallergic agents.
An initial stage in a series of reaction systems of the plasma kallikrein-kinin system is activation of the blood coagulation factor XII (FXII). W hen FXII is activated in vivo by injury or by an invading stimulation to tissues or the like, a series of enzymatic reactions of the plasma kallikrein-kinin system proceeds. Thus, the activated FXII (blood coagulation factor XII of an activated form; FXIIa) acts on the plasma prekallikrein existing in the same plasma converting it to plasma kallikrein which is an enzyme of an activated form. Then the resulting plasma kallikrein acts on a high molecular weight kininogen (HMWK) in the plasma whereupon bradykinin having various physiological activities as mentioned above is produced and liberated.
The activating reaction of FXII plays very important roles not only as a reaction for initiating the plasma kallikrein-kinin system but also as a reaction for controlling the initiating steps of various other function-controlling systems in living organisms such as the blood coagulating system, fibrinolysis system, renin-angiotensin system, complement system and arachidonate cascade. FXII has been known to be activated on a heterologous surface having a negative charge. Examples of such heterologous surfaces are kaolin, glass, Celite, dextran sulfate, collagen and acidic mucopolysaccharides. In addition, U.S. Pat. Nos. 5,599,683 and 5,648,228 disclose FXII activation with cell components such as membranes of platelets and other cells, fibronectin, elaidic acid, quercetin, rutin, sulfated glycolipids, proteoglycan, mucopolysaccharides, sodium stearate, dextran sulfate, amylose sulfate, carrageenin and proteases which activate FXII by a restricted decomposition. However, substances which activate FXII in actual living organisms have not yet been specifically identified, purified, or isolated.
The present invention provides a novel FXII-activating method which is different from the conventional method using a heterologous surface having a negative charge. An FXII-activating substance in living organisms is identified, produced in a pure or isolated form, in which interfering or competing components or other factors are substantially or completely absent, for a more faithful reproduction of an actual FXII-activating reaction in living organisms.
The present inventors have conducted an intensive study for an FXII-activating substance existing in living organisms. They have found as a result thereof that a receptor protein for globular heads of C1q which is a complement component existing on cell membranes is a substance which activates FXII whereupon the present invention has been accomplished.